Hetero-substituted acetanilide derivatives as analgesic agents

ABSTRACT

Hetero-substituted acetanilide derivatives are disclosed as analgesic agents. The compounds of the invention are useful in methods for treating a disease or condition in a mammal characterized by pain and/or fever.

CROSS-REFERENCE TO RELATED APPLICATIONS

Not applicable.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

BACKGROUND OF THE INVENTION

Para-aminophenol type nonnarcotic analgesics/antipyretics have beenknown for over a century. They act to decrease fever by an effect on thehypothalamus leading to sweating and vasodilation and inhibit the effectof pyrogens on the hypothalamic heat-regulating centers. The mechanismof the analgesic action of these agents is not fully understood.Although this analgesic action was initially thought to be peripherallymediated, current evidence supports a central mode of action(Acetaminophen-induced hypothermia in mice: evidence for a centralaction of the parent compound. Massey, Thomas E.; Walker, Robin M.;McElligott, Timothy F.; Racz, William J. Dep. Pharmacol. Toxicol.,Queen's Univ., Kingston, ON, Can. Toxicology (1982), 25(2-3), 187-200;Central analgesic effect of acetaminophen but not of aspirin. Piletta,Pierre; Porchet, Herve C.; Dayer, Pierre. Dep. Med., Univ. Hosp.,Geneva, Switz. Clin. Pharmacol. Ther. (St. Louis) (1991), 49(4), 350-4.;Acetaminophen blocks spinal hyperalgesia induced by NMDA and substanceP. Bjoerkman, R.; Hallman, K. M.; Hedner, J.; Hedner, T.; Henning, M.Pain (1994), 57(3), 259-64.). Suggested biochemistries for this centralmode of action include interaction with the L-arginine-NO pathway(Piletta, ibid), modulation of brain serotonin receptor level(Acetaminophen-induced antinociception via central 5-HT2A receptors.Srikiatkhachorn, Anan; Tarasub, Naovarut; Govitrapong, Piyarat.Neurochem. Int. (1999), 34(6), 491-498.) or inhibition of COX-3 enzymeactivity (N. V. Chandrasekharan, Hu Dai, K. Lamar Turepu Roos, Nathan K.Evanson, Joshua Tomsik, Terry S. Elton, and Daniel L. Simmons (2002)COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and otheranalgesic/antipyretic drugs: Cloning, structure, and expression. Proc.Natl. Acad. Sci. USA, 99:13926-13931, 2002). Inhibition of the COX-3enzyme, recently cloned from brain, points to the possible inhibition bythese agents of CNS prostaglandin synthesis. The antipyretic andanalgesic effects of these compounds are comparable to those of aspirin.

Para-aminophenol type nonnarcotic analgesics have been used to controlpain due to headache, earache, dysmenorrhea, arthralgia, myalgia,musculoskeletal pain, arthritis, immunizations, teething, tonsillectomy.They are also used to reduce fever in bacterial or viral infections andas a substitute for aspirin in upper GI disease, aspirin allergy,bleeding disorders, clients on anticoagulant therapy, and goutyarthritis.

Unexamined Japanese patent application 57007431 (Jan. 14, 1982)discloses various analgesic phenols. This application, however, does notdisclose or suggest the compounds of the present invention.

U.S. Pat. No. 4,532,249 discloses derivatives of para-acylaminophenolhaving analgesic activity. This patent, however, does not disclose orsuggest the compounds of the present invention.

U.S. Pat. No. 3,689,555 discloses norbornyl aminoacetanilides for usesin analgesics. This patent, however, does not disclose or suggest thecompounds of the present invention.

International Patent Applications WO 96/32100 and WO 97/33860 discloseaminoalkyl-acetamides as analgesic agents. These applications, however,do not disclose or suggest the compounds of the present invention.

U.S. Pat. No. 5,554,636 discloses cyclicsulfonamidylalkylacetamides asanalgesic agents. This patent, however, does not disclose or suggest thecompounds of the present invention.

In view of their lack of ulcerative and anticoagulation effects,paraaminophenol type nonnarcotic analgesics fill a need in analgesic andantipyretic therapies in patients with problems related to GI andcardiovascular disorders, and there is thus a continuing need for newpharmaceutical compounds of this class.

SUMMARY OF THE INVENTION

The present invention is directed to analgesic and anti-pyretic uses ofcompositions comprising a compound of Formula (I):

wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R³ is hydrogen or C₁₋₆alkanyl;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

The present invention is directed to analgesic and anti-pyretic uses ofcompositions comprising a compound of Formula (II):

wherein:

-   -   R¹ is a substituent independently selected from the group        consisting of hydrogen and C₁₋₆alkanyl;    -   R² is a substituent independently selected from the group        consisting of hydrogen, C₁₋₆alkanyl and dioxo;    -   or R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Finally, the present invention is directed to pharmaceuticalcompositions containing compounds of Formula (I) wherein R³ is hydrogenand R¹ and R² taken together form an optionally substituted pyrrole.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following underlined terms are intended to have thefollowing meanings:

“C_(a-b)” (where a and b are integers) refers to a radical containingfrom a to b carbon atoms inclusive. For example, C₁₋₃ denotes a radicalcontaining 1, 2 or 3 carbon atoms

“Alkyl:” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl , cyclopropan-1-yl ( ), prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-l-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl”,“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C₁-C₆) alkyl, with (C₁-C₃) beingparticularly preferred.

“Alkanyl:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon radical derived by the removal of one hydrogenatom from a single carbon atom of a parent alkane. Typical alkanylgroups include, but are not limited to, methanyl; ethanyl; propanylssuch as propan-1-yl, propan-2-yl, cyclopropan-1-yl, etc.; butyanyls suchas butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl,cyclobutan-1-yl, etc.; and the like. In preferred embodiments, thealkanyl groups are (C₁₋₈) alkanyl, with (C₁₋₃) being particularlypreferred.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon-carbon doublebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkene. The radical may be in either the cis or transconformation about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicmonovalent hydrocarbon radical having at least one carbon□carbon triplebond derived by the removal of one hydrogen atom from a single carbonatom of a parent alkyne. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl,etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl,etc.; and the like.

“Heteroalkyl” and Heteroalkanyl” refer to alkyl or alkanyl radicals,respectively, in which one or more carbon atoms (and any necessaryassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatoms (including any necessary hydrogen or other atoms).Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Preferred heteroatoms are O, N and S.Thus, heteroalkanyl radicals can contain one or more of the same ordifferent heteroatomic groups, including, by way of example and notlimitation, epoxy (—O—), epidioxy (—O—O—), thioether (—S—), epidithio(—SS—), epoxythio (—O—S—), epoxyimino (—O—NR′—), imino (—NR′—), biimmino(—NR′—NR′—), azino (═N—N=), azo (—N═N—), azoxy (—N—O—N—), azimino(—NR′—N═N—), phosphano (—PH—), λ⁴-sulfano (—SH₂—), sulfonyl (—S(O)₂—),and the like, where each R′ is independently hydrogen or (C₁-C₆) alkyl.

“Parent Aromatic Ring System:” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more rings are aromaticand one or more rings are saturated or unsaturated, such as, forexample, indane, indene, phenalene, etc. Typical parent aromatic ringsystems include, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like

“Aryl:” refers to a monovalent aromatic hydrocarbon radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. In preferredembodiments, the aryl group is (C₅₋₂₀) aryl, with (C₅₋₁₀) beingparticularly preferred. Particularly preferred aryl groups are phenyland naphthyl groups.

“Arylalkyl:” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal carbonatom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylakenyl and/or arylalkynyl is used. [In preferredembodiments, the arylalkyl group is (C₆₋₂₆) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁₋₆) andthe aryl moiety is (C₅₋₂₀). In particularly preferred embodiments thearylalkyl group is (C₆₋₁₃), e.g., the alkanyl, alkenyl or alkynyl moietyof the arylalkyl group is (C₁₋₃) and the aryl moiety is (C₅₋₁₀). Evenmore preferred arylalkyl groups are phenylalkanyls.

“Alkanyloxy:” refers to a saturated branched, straight-chain or cyclicmonovalent hydrocarbon alcohol radical derived by the removal of thehydrogen atom from the hydroxide oxygen of the alcohol. Typicalalkanyloxy groups include, but are not limited to, methanyl; ethanyloxy;propanyloxy groups such as propan-1-yloxy (CH₃CH₂CH₂O—), propan-2-yloxy((CH₃)₂CHO—), cyclopropan-1-yloxy, etc.; butyanyloxy groups such asbutan-1-yloxy, butan-2-yloxy, 2-methyl-propan-1-yloxy,2-methyl-propan-2-yloxy, cyclobutan-1-yloxy, etc.; and the like. Inpreferred embodiments, the alkanyloxy groups are (C₁₋₈) alkanyloxygroups, with (C₁₋₃) being particularly preferred.

“Parent Heteroaromatic Ring System:” refers to a parent aromatic ringsystem in which one carbon atom is replaced with a heteroatom.Heteratoms to replace the carbon atoms include N, O, and S. Specificallyincluded within the definition of “parent heteroaromatic ring systems”are fused ring systems in which one or more rings are aromatic and oneor more rings are saturated or unsaturated, such as, for example,arsindole, chromane, chromene, indole, indoline, xanthene, etc. Typicalparent heteroaromatic ring systems include, but are not limited to,carbazole, imidazole, indazole, indole, indoline, indolizine, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like.

“Heteroaryl:” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, radicals derived from carbazole, imidazole, indazole,indole, indoline, indolizine, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, purine,pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In preferred embodiments, the heteroaryl group is a 5-20 memberedheteroaryl, with 5-10 membered heteroaryl being particularly preferred.

“Cycloheteroalkyl:” refers to a saturated or unsaturated monocyclic orbicyclic alkyl radical in which one carbon atom is replaced with N, O orS. In certain specified embodiments the cycloheteroalkyl may contain upto four heteroatoms independently selected from N, O or S. Typicalcycloheteroalkyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkyl is a 3-6 membered cycloheteroalkyl.

“Cycloheteroalkanyl:” refers to a saturated monocyclic or bicyclicalkanyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkanyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkanyl moieties include, but are not limited to, radicalsderived from imidazolidine, morpholine, piperazine, piperidine,pyrazolidine, pyrrolidine, quinuclidine, and the like. In preferredembodiments, the cycloheteroalkanyl is a 3-6 memberedcycloheteroalkanyl.

“Cycloheteroalkenyl:” refers to a saturated monocyclic or bicyclicalkenyl radical in which one carbon atom is replaced with N, O or S. Incertain specified embodiments the cycloheteroalkenyl may contain up tofour heteroatoms independently selected from N, O or S. Typicalcycloheteroalkenyl moieties include, but are not limited to, radicalsderived from imidazoline, pyrazoline, pyrroline, indoline, pyran, andthe like. In preferred embodiments, the cycloheteroalkanyl is a 3-6membered cycloheteroalkanyl.

“Substituted:” refers to a radical in which one or more hydrogen atomsare each independently replaced with the same or differentsubstituent(s). Typical substituents include, but are not limited to,—X, —R, —O⁻, ═O, —OR, —O—OR, —SR, —S⁻, ═S, —NRR, ═NR, —CX₃, —CN, —OCN,—SCN, —NCO, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHOH, —S(O)₂O⁻, —S(O)₂OH,—S(O)₂R, —P(O)(O⁻)₂, —P(O)(OH)₂, —C(O)R, —C(O)X, —C(S)R, —C(S)X,—C(O)OR, —C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR and—C(NR)NRR, where each X is independently a halogen (preferably —F, —Clor —Br) and each R is independently —H, alkyl, alkanyl, alkenyl,alkynyl, alkylidene, alkylidyne, aryl, arylalkyl, arylheteroalkyl,heteroaryl, heteroarylalkyl or heteroaryl-heteroalkyl, as definedherein. Preferred substituents include hydroxy, halogen, C₁₋₈alkyl,C₁₋₈alkanyloxy, fluorinated alkanyloxy, fluorinated alkyl,C₁₋₈alkylthio, C₃₋₈cycloalkyl, C₃₋₈cycloalkanyloxy, nitro, aminoC₁₋₈alkylamino, C₁₋₈dialkylamino, C₃₋₈cycloalkylamino, cyano, carboxy,C₁₋₇alkanyloxycarbonyl, C₁₋₇alkylcarbonyloxy, formyl, carbamoyl, phenyl,aroyl, carbamoyl, amidino, (C₁₋₈alkylamino)carbonyl, (arylamino)carbonyland aryl(C₁₋₈alkyl)carbonyl

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

Throughout this disclosure, the terminal portion of the designated sidechain is described first, followed by the adjacent functionality towardthe point of attachment. Thus, for example, a“phenylC₁₋₆alkanylaminocarbonylC₁₋₆alkyl” substituent refers to a groupof the formula

The present invention is directed to analgesic and anti-pyretic uses ofcompositions comprising a compound of Formula (I):

wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R³ is hydrogen or C₁₋₆alkanyl;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Embodiments of the present invention include those wherein for compoundsof formula (I):

-   -   a) R¹ and R² taken together with the atoms to which they are.        attached form a 5 to 10 membered cycloheteroalkanyl radical,        wherein, in addition to the heteroatom N, said radical may        optionally contain 1 to 3 additional heteroatoms, independently        selected from the group consisting of O, N and S; additionally,        said radical may be further optionally substituted with one to        three substituents independently selected from the group        consisting of C₁₋₆alkanyl and oxo;    -   b) R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered cycloheteroalkenyl radical,        wherein, in addition to the heteroatom N, said radical may        optionally contain 1 to 3 additional heteroatoms, independently        selected from the group consisting of O, N and S; additionally,        said radical may be further optionally substituted with one to        three substituents independently selected from the group        consisting of C₁₋₆alkanyl and oxo;    -   c) R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered heteroaryl radical, wherein, in        addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   d) R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycli heteroalkyl and a 5 to 10 membered        heteroaryl; additionally, said radical may be further optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₆alkanyl and oxo;    -   e) R³ is hydrogen;    -   f) R⁴ is hydrogen;    -   g) n is 1; and    -   h) combinations of a) through g) above.        Thus, exemplary embodiments of the present invention are as        described below.

An embodiment of the present invention is directed to analgesic andanti-pyretic uses of compositions comprising a compound of Formula (I)wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered cycloheteroalkanyl radical,        wherein, in addition to the heteroatom N, said radical may        optionally contain 1 to 3 additional heteroatoms, independently        selected from the group consisting of O, N and S; additionally,        said radical may be further optionally substituted with one to        three substituents independently selected from the group        consisting of C₁₋₆alkanyl and oxo;    -   R³ is hydrogen or C₁₋₆alkanyl;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to analgesic andanti-pyretic uses of compositions comprising a compound of Formula (I)wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered cycloheteroalkenyl, wherein, in        addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R³ is hydrogen or C₁₋₆alkanyl;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (I) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered heteroaryl radical, wherein, in        addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R³ is hydrogen or C₁₋₆alkanyl;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (I) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl;        additionally, said radical may be further optionally substituted        with one to three substituents independently selected from the        group consisting of C₁₋₆alkanyl and oxo;    -   R³ is hydrogen or C₁₋₆alkanyl;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still yet another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (I) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R³ is hydrogen;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (I) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R³ is hydrogen or C₁₋₆alkanyl;    -   R⁴ is hydrogen;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still yet another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (I) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R³ is hydrogen or C₁₋₆alkanyl;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is 1;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

The present invention is directed to analgesic and anti-pyretic uses ofcompositions comprising a compound of Formula (II):

wherein:

-   -   R¹ is a substituent independently selected from the group        consisting of hydrogen and C₁₋₆alkanyl;    -   R² is a substituent independently selected from the group        consisting of hydrogen, C₁₋₆alkanyl and dioxo;    -   or R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Embodiments of the present invention include those wherein for compoundsof Formula (II):

-   -   a) R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered cycloheteroalkanyl, wherein, in        addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   b) R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered cycloheteroalkenyl radical,        wherein, in addition to the heteroatom N, said radical may        optionally contain 1 to 3 additional heteroatoms, independently        selected from the group consisting of O, N and S; additionally,        said radical may be further optionally substituted with one to        three substituents independently selected from the group        consisting of C₁₋₆alkanyl and oxo;    -   c) R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered heteroaryl radical, wherein, in        addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   d) R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycli heteroalkyl and a 5 to 10 membered        heteroaryl; additionally, said radical may be further optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₆alkanyl and oxo;    -   e) R⁴ is hydrogen;    -   f) n is 1; and    -   g) combinations of a) through f) above.        Thus, exemplary embodiments of the present invention are as        described below.

An embodiment of the present invention is directed to analgesic andanti-pyretic uses of compositions comprising a compound of Formula (II)wherein:

-   -   R¹ and R²taken together with the atoms to which they are        attached form a 5 to 10 membered cycloheteroalkanyl radical,        wherein, in addition to the heteroatom N, said radical may        optionally contain 1 to 3 additional heteroatoms, independently        selected from the group consisting of O, N and S; additionally,        said radical may be further optionally substituted with one to        three substituents independently selected from the group        consisting of C₁₋₆alkanyl and oxo;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to analgesic andanti-pyretic uses of compositions comprising a compound of Formula (II)wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered cycli heteroalkenyl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (II) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a 5 to 10 membered heteroaryl radical, wherein, in        addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (II) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl;        additionally, said radical may be further optionally substituted        with one to three substituents independently selected from the        group consisting of C₁₋₆alkanyl and oxo;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (II) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R⁴ is hydrogen;    -   n is an integer from 1 to 3;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Still yet another embodiment of the present invention is directed toanalgesic and anti-pyretic uses of compositions comprising a compound ofFormula (II) wherein:

-   -   R¹ and R² taken together with the atoms to which they are        attached form a radical selected from the group consisting of a        5 to 10 membered cycloheteroalkanyl, 5 to 10 membered        cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein,        in addition to the heteroatom N, said radical may optionally        contain 1 to 3 additional heteroatoms, independently selected        from the group consisting of O, N and S; additionally, said        radical may be further optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₆alkanyl and oxo;    -   R⁴ is a substituent selected from the group consisting of        hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy, fluorinated alkanyl,        fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino,        C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;    -   n is 1;        and enantiomers, diastereomers, tautomers, solvates, or        pharmaceutically acceptable salts thereof.

Another embodiment of the present invention is directed to compositionscomprising a compound of Formula (I) or Formula (II) wherein saidcompound is selected from the group consisting of:

Pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide;

(S)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide;

N-(4-Hydroxy-phenyl)-2-mercapto-acetamide;

N-(4-Hydroxy-phenyl)-2-methylsulfanyl-acetamide;

N-(4-Hydroxy-phenyl)-2-methanesulfonyl-acetamide;

(R)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide;

1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide;

1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide;

5-Methyl-1H-pyrazole-3-carboxylic acid (4-hydroxy-phenyl)-amide;and

3H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide.

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J.Pharm.Sci., 1997 (January), 66, 1, 1). Other salts well known to thosein the art may, however, be useful in the preparation of compoundsaccording to this invention or of their pharmaceutically acceptablesalts. Representative organic or inorganic acids include, but are notlimited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric,nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic,maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Even though the compounds of the present invention (including theirpharmaceutically, acceptable salts and pharmaceutically acceptablesolvates) can be administered alone, they will generally be administeredin admixture with a pharmaceutical carrier, excipient or diluentselected with regard to the intended route of administration andstandard pharmaceutical or veterinary practice. Thus, the presentinvention is directed to pharmaceutical and veterinary compositionscomprising compounds of Formula (I) and one or more pharmaceuticallyacceptable carriers, excipients or diluents.

By way of example, in the pharmaceutical and veterinary compositions ofthe present invention, the compounds of the present invention may beadmixed with any suitable binder(s), lubricant(s), suspending agent(s),coating agent(s), and/or solubilising agent(s).

Tablets or capsules of the compounds may be administered singly or twoor more at a time, as appropriate. It is also possible to administer thecompounds in sustained release formulations.

Alternatively, the compounds of the general Formula (I) can beadministered by inhalation or in the form of a suppository or pessary,or they may be applied topically in the form of a lotion, solution,cream, ointment or dusting powder. An alternative means of transdermaladministration is by use of a skin patch. For example, they can beincorporated into a cream consisting of an aqueous emulsion ofpolyethylene glycols or liquid paraffin. They can also be incorporated,at a concentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilisers and preservatives as may be required.

For some applications, preferably the compositions are administeredorally in the form of tablets containing excipients such as starch orlactose, or in capsules or ovules either alone or in admixture withexcipients, or in the form of elixirs, solutions or suspensionscontaining flavouring or coloring agents.

The compositions (as well as the compounds alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly or subcutaneously. In this case, the compositions willcomprise a suitable carrier or diluent.

For parenteral administration, the compositions are best used in theform of a sterile aqueous solution which may contain other substances,for example enough salts or monosaccharides to make the solutionisotonic with blood.

For buccal or sublingual administration the compositions may beadministered in the form of tablets or lozenges which can be formulatedin a conventional manner.

By way of further example, pharmaceutical and veterinary compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate the major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those skilled in that art. To be administered inthe form of a transdermal delivery system, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

A therapeutically effective amount for use of the instant compounds or apharmaceutical composition thereof comprises a dose range of from about0.01 mg to about 15,000 mg, in particular from about 1 mg to about 5000mg or, more particularly from about 500 mg to about 4000 mg of activeingredient per day for an average (70 kg) human.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing, 0.01, 10.0, 50.0, 100, 150,200, 250 and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The above dosages are thusexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as analgesics or anti-pyretics is required for a subjectin need thereof.

The invention also provides a pharmaceutical or veterinary pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical and veterinary compositions of theinvention. Optionally associated with such container(s) can be a noticein the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration.

The compounds of Formulas (I) and (II) are useful in methods fortreating a disease or condition in a mammal characterized by pain and/orfever.

Such methods comprises administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound, salt orsolvate of Formulas (I) or (II). In particular, the compounds ofFormulas (I) and (II) are useful for in methods for control of pain dueto headache, earache, dysmenorrhea, arthralgia, myalgia, musculoskeletalpain, arthritis, immunizations, teething, tonsillectomy. They are alsoused to reduce fever in bacterial or viral infections and as asubstitute for aspirin in upper GI disease, aspirin allergy, bleedingdisorders, subjects on anticoagulant therapy, and gouty arthritis.

In another embodiment, the compounds of Formulas (I) and (II) are usefulin treatment of inflammation.

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated in the schemes that follows. Since the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used in the schemes is well within the skillof persons versed in the art.

The hetero-substituted acaetanilide analogues of formula (I) or formula(II) that comprise this invention are synthesized using the generalchemical methods shown in Schemes A through E.

Compounds of Formula (I) are prepared by coupling commercially availableanilines A1 with commercially available carboxylic acids A2 in thepresence of a coupling reagent such as HBTU, also in the presence of abase such as DIPEA or TEA, also in the presence of a suitable solventsuch as DMF which provides protected intermediates A3.

The benzyl protecting group is then removed under hydrogenationconditions under pressures of about 55 psi in the presence of a suitablepaladdium catalyst such as 10% palladium on carbon which provides thetarget compounds of Formula (I).

Compounds of Formula (II) are prepared by coupling commerciallyavailable anilines A1 with commercially available carboxylic acids B2 inthe presence of a coupling reagent such as HBTU, also in the presence ofa base such as DIPEA or TEA, also in the presence of a suitable solventsuch as DMF which provided protected intermediates B2.

The benzyl protecting group is then removed under hydrogenationconditions under pressures of about 55 psi in the presence of a suitablepalladium catalyst such as 10% palladium on carbon which provided thetarget compounds of Formula (II).

In the case of certain imidazole compounds, the above described schemeswere modified as shown in Scheme C. The carboxylic acid startingmaterial is replaced with the 5-H, 10H-diimidazo[1,5-a,1′,5′-d]pyrazine-5,10-dione C1 which is optionally substituted with R⁵,wherein R⁵ is C₁₋₆alkyl or oxo, which when reacted directly withanilines A1 upon heating provides the intermediates C2. The protectinggroup is removed as previously described in schemes A and B to providescompounds C3.

Compounds of Formula (I) may also be prepared by directly coupling a4-hydroxy aniline D1 with an acid chloride D2 as shown in Scheme D.

Compounds of Formula (II) may also be prepared by directly coupling a4-hydroxy aniline E1 with an acid chloride E2 as shown in Scheme E.

It is generally preferred that the respective product of each processstep be separated. from other components of the reaction mixture andsubjected to purification before its use as a starting material in asubsequent step. Separation techniques typically include evaporation,extraction, precipitation and filtration. Purification techniquestypically include column chromatography (Still, W. C. et. al., J. Org.Chem. 1978, 43, 2921), thin-layer chromatography, crystallization anddistillation. The structures of the final products, intermediates andstarting materials are confirmed by spectroscopic, spectrometric andanalytical methods including nuclear magnetic resonance (NMR), massspectrometry (MS) and liquid chromatography (HPLC). In the descriptionsfor the preparation of compounds of this invention, ethyl ether,tetrahydrofuran and dioxane are common examples of an ethereal solvent;benzene, toluene, hexanes and cyclohexane are typical hydrocarbonsolvents and dichloromethane and dichloroethane are representativehalogenhydrocarbon solvents. In those cases where the product isisolated as the acid addition salt the free base may be obtained bytechniques known to those skilled in the art. In those cases in whichthe product is isolated as an acid addition salt, the salt may containone or more equivalents of the acid.

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described above and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

EXAMPLES Example 1 Pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide

A. Pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide.

A solution of pyridine-2-carboxylic acid (2.0 g, 8.48 mmol) inN,N-dimethylformamide (DMF) was treated withO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (3.5 g, 9.33 mmol) and N,N-diisopropylethylamine (DIEA) (0.742mL, 32.7 mmol) and stirred at room temperature for 10 min.4-Benzyloxyaniline hydrochloride (2.0 g, 8.48 mmol) was added to thesolution, and stirring was continued for an additional 30 min. Thesolution was poured into a saturated aqueous solution of sodiumbicarbonate on ice. Mechanically mixing the gummy residue in the bottomof the flask caused it to solidify. The product was collected byfiltration, washed with water and dried to give a beige solid, 2.46 g(95%), which was used without further purification in the subsequentreaction. MS m/z 305 (MH⁺). ¹H NMR(CDCl₃) δ 5.07 (s, 2H), 7.0 (d, 2H),7.30-7.50 (m, 6H), 7.70 (d, 2H), 7.92 (t, 1H), 8.32 (d, 1H) and 8.58 (d,1H).

B. Pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide.

A solution of pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide (7.7g, 25.3 mmol) in 90% ethanol (110 mL) was hydrogenated (60 psi) over 10%palladium on carbon (0.8 g) at 50° C. for 4 hours. The catalyst wasremoved by filtration, and the solvent was evaporated in vacuo. Theresidue was purified by flash chromatography on silica gel, usingmethanol/dichloromethane (DCM),5/95, as the eluant, to give the productas a beige solid, 2.54 g (47%). MS m/z 215 (MH⁺). ¹H NMR(DMSO-d₆) δ 6.76(d, 2H), 7.54 to 7.76 (m, 3H), 8.05 (t, 1H), 8.14 (d, 1H), 8.72 (d, 1H),9.30 (s, 1H) and 10.41 (s, 1H). Anal. calcd for C₁₂H₁₀N₂O₂: C, 67.28; H,4.71; N, 13.08. Found: C, 66.99; H, 4.56; N, 12.81.

Example 2 N-(4-Hydroxy-phenyl)-2-methanesulfonyl-acetamide

A. N-(4-Benzyloxy-phenyl)-2-methanesulfonyl-acetamide

A solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol),methanesulfonylacetic acid (2.35 g, 17.0 mmol) and HBTU (6.89 g, 18.2mmol) in DMF (70 mL) was stirred at ambient temperature one minute. DIEA(6.5 mL, 37.2 mmol) was added all at once, and the resultant solutionwas stirred at ambient temperature. The solution was poured into water,and the product crystallized. The product, 5.4 g (99%), was collected byfiltration and was used without any further purification in thesubsequent reaction. MS m/z 320 (MH⁺). ¹H NMR(DMSO-d₆) δ 3.17 (s, 3H),4.25 (s, 2H), 5.07 (s, 2H), 7.00 (d, 2H), 7.32-7.55 (m, 7H) and 10.32(s, 1H).

B. N-(4-Hydroxy-phenyl)-2-methanesulfonyl-acetamide

This compound was prepared fromN-(4-benzyloxy-phenyl)-2-methanesulfonyl-acetamide, using the samemethod used to prepare of pyridine-2-carboxylic acid(4-hydroxyphenyl)amide. The product was purified by flashchromatography, on silica gel, eluted with 5 to 10% methanol in DCM, togive the product, 3.45 g (92%) as a colorless solid. MS m/z 230 (MH⁺).¹H NMR(DMSO-d₆) δ 3.18 (s, 3H), 4.22 (s, 2H), 6.72 (d, 2H), 7.36 (d,2H), 9.35(br s, 1H) and 10.17 (s, 1H). Anal. calcd for C₉H₁₁N₄OS: C,47.15; H, 4.84; N, 6.11. Found: C, 47.04; H, 4.79; N, 6.04.

Example 3 1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide

A. 1H-Pyrrole-2-carboxylic acid (4-benzyloxy-phenyl)-amide

This compound was prepared from 4-benzyloxyaniline (4.0 g, 17 mmol) andpyrrole-2-carboxylic acid (1.98 g, 17.8 mmol), using the same methodused to prepare pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide. Theproduct was purified by flash chromatography, on silica gel, using 5%methanol in DCM as the eluant, to give the product as a colorless solid,2.6 g (50%). MS m/z 293 (MH⁺). ¹H NMR(DMSO-d₆) δ 5.04 (s, 2H), 6.13 (m,1H), 6.95-7.05 (m, 4H), 7.28-7.45 (m, 5H), 7.65 (d, 2H), 9.7 (s, 1H) and11.65 (s,1H).

B. 1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide

This compound was prepared from 1H-pyrrole-2-carboxylic acid(4-benzyloxyphenyl)-amide (2.5 g, 8.55 mmol), using the same method usedto prepare of pyridine-2-carboxylic acid (4-hydroxyphenyl)amide. Theproduct was purified by flash chromatography, on silica gel, eluted with5 to 7.5% methanol in DCM, to give the product as a colorless solid,1.47 g (85%). MS m/z 203 (MH⁺). ¹H NMR(DMSO-d₆) δ 6.14 (m, 1H), 6.72 (d,2H), 6.92 (m, 1H), 6.99 (d, 1H), 7.47 (d, 2H), 9.19 (s, 1H). Anal. calcdfor C₁₁H₁₀N₂O₂: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.15; H, 4.83;N, 13.81.

Example 4 (S)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide

A. (S)-2-(4-Benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidbenzyl ester

This compound was prepared from 4-benzyloxyaniline hydrochloride (4.0 g,17.0 mmol) and (−)-N-carbobenzyloxy-1-proline (4.44 g, 17.8 mmol), usingthe same method to prepare pyridine-2-carboxylic acid(4-benzyloxyphenyl)amide, to give the product as a colorless solid, 7.51g (98%), which was used without further purification in the subsequentstep. MS m/z 431 (MH⁺). ¹H NMR(CDCl₃) δ 1.83-2.61 (m, 4H), 3.44-3.65 (m,2H), 4.40-4.55 (m,1H), 5.03 (s, 2H), 5.22 (br s, 2H), 6.90 (d, 2H) and7.20-7.45 (m, 12H).

B. (S)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide

A suspension of(S)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzylester (7.0 g, 16.3 mmol) in ethanol/water (70 mL/7 mL) was hydrogenatedover 10% palladium on carbon (0.41 g) at 55 psi of hydrogen, at 50° C.,for 5 hours. The mixture was cooled, and the catalyst was removed byfiltration. The solvent was evaporated in vacuo. The residue wasdissolved in hot ethanol (30 mL) and treated with a saturated solutionof hydrogen chloride in ethanol (3 mL). The product crystallized as thehydrochloride salt, 1.27 g (32%), a colorless solid. MS m/z 207 (MH⁺).¹H NMR(DMSO-d₆) δ 1.92 (m, 3H), 2.43 (m, 1H), 3.28 (m, 2H), 4.31 (m,1H), 6.77 (d, 2H), 7.47 (d, 2H), 9.44 (br s, 1H) and 10.75 (s, 1H).Anal. calcd for C₁₁H₁₄N₂O₂: C, 54.44; H, 6.23; N, 11.54. Found: C,54.28; H, 6.06; N, 11.66.

Example 5 (R)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide

A. (R)-2-(4-Benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidbenzyl ester

This compound was prepared from 4-benzyloxyaniline hydrochloride (4.0 g,17.0 mmol) and (+)-N-carbobenzyloxy-d-proline (4.44 g, 17.8 mmol), usingthe same method to prepare pyridine-2-carboxylic acid(4-benzyloxyphenyl)amide, to give the product as a colorless solid,which was used without further purification in the subsequent step. ¹HNMR(DMSO-d₆) δ61.80-1.95 (m, 3H), 2.10-2.27 (m, 1H), 3.35-3.55 (m, 2H),4.33 (m, 1H), 5.0 (m, 4H), 6.95 (d, 2H), 7.12-7.53 (m, 12H) and 9.95 (d,1H).

B. (R)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide

This compound was prepared from(R)-2-(4-benzyloxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzylester, using the same method used to prepare(S)-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide. The freebase was dissolved in hot isopropanol (20 mL) and treated with asaturated solution of hydrogen chloride in isopropanol (3 mL). Theproduct crystallized as the hydrochloride salt, 2.43 g (59% for 2steps). MS m/z 207 (MH⁺). ¹H NMR(DMSO-d₆) δ 1.93 (m, 3H), 2.39 (m, 1H),3.26 (m, 2H), 4.35 (t, 1H), 6.76 (d, 2H), 7.43 (d, 2H), 9.43 (br s, 1H)and 10.70 (s, 1H). Anal. calcd for C₁₁H₁₄N₂O₂: C, 54.44; H, 6.23; N,11.54. Found: C, 54.33; H, 6.26; N, 11.57.

Example 6 1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide

A. 1H-Indazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide

DIEA (9.3 mL, 53.4 mmol) was added to a solution of 4-benzyloxyanilinehydrochloride (4.0 g, 17.0 mmol), indazole-3-carboxylic acid (2.89 g,17.8 mmol) and HBTU (7.1 g, 18.7 mmol) in DMF (60 mL), and the resultingsolution was stirred at ambient temperature for 24 hours. The solutionwas heated to 70° C. for 4 hours, and then poured into a mixture ofsaturated aqueous sodium bicarbonate on ice. The product, an off whitesolid, 6.0 g, was collected by filtration, washed with water and usedwithout further purification in the subsequent reaction. MS m/z 344(MH⁺). ¹H NMR(DMSO-d₆) δ 5.11 (s, 2H), 7.02 (d, 2H), 7.26-7.48 (m, 7H),7.67 (d, 1H), 7.75 (d, 2H), 7.81 (d, 1H), 8.24 (d, 1H) and 10.24 (s,1H).

B. 1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide

This compound was prepared from 1H-Indazole-3-carboxylic acid(4-benzyloxy-phenyl)-amide, using the same method used to prepare(S)-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide. The productwas purified by flash chromatography, on silica gel, eluted with 5 to10% methanol in DCM, to give the product as an off white solid, 2.6 g(60% for 2 steps). MS m/z 254 (MH⁺). ¹H NMR(DMSO-d₆) δ 6.74 (d, 2H),7.26-7.34 (m, 1H), 7.43-7.51 (m, 1H), 7.67-7.73 (m, 3H), 8.24 (d, 1H),9.25 (s, 1H), 10.10 (s, 1H) and 13.72 (s, 1H). Anal. calcd forC₁₄H₁₁N₃O₂: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.15; H, 4.20; N,16.82.

Example 7 5-Methyl-1H-pyrazole-3-carboxylic acid(4-hydroxy-phenyl)-amide

A. 5-Methyl-1H-pyrazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide

This compound was prepared from 4-benzyloxyaniline hydrochloride (4.0 g,17.0 mmol) and 5-methylpyrazole-2-carboxylic acid (2.25 g, 17.8 mmol),using the same method used to prepare pyridine-2-carboxylic acid(4-benzyloxyphenyl)amide, to give the product as a solid. The productwas used without further purification in the subsequent reaction. MS m/z308 (MH⁺). ¹H NMR(CDCl₃+MeOD-d₄) δ 2.34 (s, 3H), 5.06 (s, 2H), 6.62 (s,1H), 6.96 (d, 2H), 7.31 (m, 7H) and 7.58 (d, 1H).

B. 5-Methyl-1H-pyrazole-3-carboxylic acid (4-hydroxy-phenyl)-amide

This compound was prepared from 5-methyl-1H-pyrazole-3-carboxylic acid(4-benzyloxy-phenyl)-amide, using the same method used to preparepyridine-2-carboxylic acid (4-hydroxyphenyl)amide. The product waspurified by flash chromatography, on silica gel, eluted with 5 to 10%methanol in DCM as the eluant, to give the product as an off whitesolid, 2.75 g (68%). MS m/z 218 MH⁺). ¹H NMR(DMSO-d₆) δ 2.28 (s, 3H),6.47 (s, 1H), 6.71 (d, 2H), 7.55 (d, 2H), 9.19 (s, 1H), 9.67 (s, 1H) and13.00 (s, 1H). Anal. calcd for C₁₁H₁₁N₃O₂; C, 60.08; H, 5.17; N, 19.10.Found: C, 60.00; H, 4.99; N, 19.25.

Example 8 3H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide

A. 3-H-Imidazole-4-carboxylic acid (4-benzyloxyphenyl)amide.

An intimate mixture of 4.25 g (22 mmol) of 5-H, 10H-diimidazo[1,5-a,1′,5′-d]pyrazine-5,10-dione and 9.04 g (45 mmol) of 4-benzyloxyanilinewas heated on a steam bath for 30 min. The residue was flashchromatographed with 5% MeOH in CH₂Cl₂ to give 4.8 g of the titlecompound (66% yield). MS m/z 294 (MH⁺). ¹H NMR(CDCl₃) δ 5.07 (s, 2H),7.0 (d, 2H), 7.30-7.50 (m, 3H), 7.7-7.8 (m, 4H), 9.8 (s 1H), 12.6 (s, ₁H).

B. 3-H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide.

A solution of 3-H-imidazole-4-carboxylic acid (4-benzyloxyphenyl)amide.(3.3 g, 11.2 mmol) in glacial acetic acid (70 mL) was hydrogenated (60psi) over g of 10% palladium on carbon (0.3 g) at 25° C. for 18 hours.The catalyst was removed by filtration, and the solvent was evaporatedin vacuo. The residue was stirred with NaHCO₃ solution and the solidcollected. There was obtained 2.4 g (100% yield) of the title compoundas a yellow solid. MS m/z 204 (MH⁺). ¹ H NMR(DMSO-d₆) δ 6.7 (dd, 2H),7.5 (dd, 2H), 7.7 (s, 1H), 7.8 (s, 1H), 9.1 (s, 1H), 9.6 (s, 1H) and12.5 (s, 1H).

Example 9 N-(4-Hydroxy-phenyl)-2-mercapto-acetamide

A mixture of 4-aminophenol (4.0 g, 36.7 mmol) and mercaptoacetic acid(2.93 g, 38.5 mmol) under an atmosphere of carbon dioxide was heated toreflux (oil bath temperature ˜120° C.) for 4 hours. The mixture wascooled and diluted with 2 N hydrochloric acid (˜100 mL). A purple solid,1.3 g, was collected by filtration and washed with water. The productwas purified by flash chromatography, on silica gel, eluted with 5 to10% methanol in DCM, to give a colorless solid, 1.03 g (15%). MS m/z 184(MH⁺). ¹H NMR(DMSO-d₆) δ 2.08 (t, 1H), 3.24 (s, 2H), 6.70 (d, 2H), 7.35(d, 2H), 9.21 (br s, 1H) and 9.83 (s, 1H). Anal. calcd for C₈H₉NO₂S: C,52.44; H, 4.95; N, 7.64. Found: C, 52.57; H, 4.95; N, 7.40.

Biological Examples Example 1 Mouse Abdominal Irritant Test (MAIT)

Male CD1 mice (weighing from 18-24 g) are used to determine theantinociceptive effects associated with the compositions of theinvention. The mice are all dosed orally with the compounds specified,dissolved in distilled water or suspended in 0.5% Methocel™(hydroxypropyl methylcellulose) in water. The dosing volume is 10 mL/kg.

The procedure used in detecting and comparing the analgesic activity ofdifferent classes of analgesic drugs for which there is a goodcorrelation with human efficacy is the prevention ofacetylcholine-induced abdominal constriction in mice (H. Collier et al.,Br. J. Pharmacol., 32, 295 (1968)).

Mice, intubated with various doses of the compound or vehicle such asdistilled water, or distilled water 0.5% Methocel™ (hydroxypropylmethylcellulose) in water, are injected intraperitoneally with achallenge dose of acetylcholine bromide. The acetylcholine is completelydissolved in distilled water at a concentration of 5.5 mg/kg andinjected at the rate of 0.20 mL/20 g. For scoring purposes, an“abdominal constriction” is defined as a contraction of the abdominalmusculature accompanied by arching of the back and extension of thelimbs. The mice are observed for 10 minutes for the presence or absenceof the abdominal constriction response beginning immediately afterreceiving the acetylcholine dose, administered at a certain time afterthe oral administration of the test drug or vehicle. Each mouse is usedonly once.

The percent of inhibition of this response is calculated as follows:% Inhibition=100×(Number of Nonresponders)/(Number of Animals in Group)

TABLE 2 Antinociceptive Effect in Mouse Abdominal Irritant Test CompoundEffect @ 300 mg/kg Pyridine-2-carboxylic acid (4- 60.0hydroxy-phenyl)-amide (S)-Pyrrolidine-2-carboxylic acid (4- 40.0hydroxy-phenyl)-amide N-(4-Hydroxy-phenyl)-2- 45.0methylsulfanyl-acetamide N-(4-Hydroxy-phenyl)-2- 40.0methanesulfonyl-acetamide (R)-Pyrrolidine-2-carboxylic acid 20.0(4-hydroxy-phenyl)-amide 1H-Pyrrole-2-carboxylic acid (4- 86.7hydroxy-phenyl)-amide 1H-Indazole-3-carboxylic acid (4- 20.0hydroxy-phenyl)-amide 5-Methyl-1H-pyrazole-3-carboxylic 73.3 acid(4-hydroxy-phenyl)-amide N-(4-Hydroxy-phenyl)-2-mercapto- 40.0 acetamide

Example 2 Antipyretic Evaluation of Compounds

Groups of 10 male rats are weighed, color-coded, rectal temperaturestaken (24 hours±15 minutes prior to dose administration) and recorded.Food is removed but water remains available ad libitum. Each rat isinjected subcutaneously into the central dorsal region with 5 ml of a15% yeast suspension. Twenty-three hours (±15 minutes) after yeastinjection, body weights and rectal temperatures are taken and recorded.Twenty-four hours (±15 minutes) after yeast injection, the vehicle andtest articles are administered orally. Temperatures are taken andrecorded one hour (±5 minutes) following test article or vehicleadministration.

The mean rectal temperatures for the test article and vehicle controlgroups are calculated at 23 and 25 hours (±15 minutes) and subjected toan ANOVA followed by a Tukey HSD Multiple Comparison Test(p≦0.05)—Systat, version 9.0.

As represented in Table 3, the oral administration of compound 1, at 600mg/kg produces a statistically significant (p≦0.05) decrease in bodytemperature in rats relative to the vehicle-treated group. TABLE 3Antipyretic Effect in Rats Antipyresis Compound deg C. @ 600 mpkPyridine-2-carboxylic acid (4- −2.17 hydroxy-phenyl)-amide

1. A method of controlling pain or fever in a subject in need thereofcomprising administering to the subject a compound of Formula (I):

wherein: ¹ and R² taken together with the atoms to which they areattached form a radical selected from the group consisting of a 5 to 10membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl and a 5to 10 membered heteroaryl, wherein, in addition to the heteroatom N,said radical may optionally contain 1 to 3 additional heteroatoms,independently selected from the group consisting of O, N and S;additionally, said radical may be further optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₆alkanyl and oxo; ³ is hydrogen or C₁₋₆alkanyl; ⁴ is asubstituent selected from the group consisting of hydrogen, C₁₋₆alkanyl,C₁₋₆alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy, halogen,hydroxyl, nitro, amino, C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano;n is an integer from 1 to 3; and enantiomers, diastereomers, tautomers,solvates, or pharmaceutically acceptable salts thereof.
 2. The method ofclaim 1 wherein R¹ and R² taken together with the atoms to which theyare attached form a 5 to 10 membered cycloheteroalkanyl radical,wherein, in addition to the heteroatom N, said radical may optionallycontain 1 to 3 additional heteroatoms, independently selected from thegroup consisting of O, N and S; additionally, said radical may befurther optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl and oxo;3. The method of claim 1 wherein R¹ and R² taken together with the atomsto which they are attached form a 5 to 10 membered cycloheteroalkenylradical, wherein, in addition to the heteroatom N, said radical mayoptionally contain 1 to 3 additional heteroatoms, independently selectedfrom the group consisting of O, N and S; additionally, said radical maybe further optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl and oxo;4. The method of claim 1 wherein R¹ and R² taken together with the atomsto which they are attached form a 5 to 10 membered heteroaryl radical,wherein, in addition to the heteroatom N, said radical may optionallycontain 1 to 3 additional heteroatoms, independently selected from thegroup consisting of O, N and S; additionally, said radical may befurther optionally substituted with one to three substituentsindependently selected from the group consisting of C₁₋₆alkanyl and oxo;5. The method of claim 1 wherein R¹ and R² taken together with the atomsto which they are attached form a radical selected from the groupconsisting of a 5 to 10 membered cycloheteroalkanyl, 5 to 10 memberedcycloheteroalkenyl and a 5 to 10 membered heteroaryl; additionally, saidradical may be further optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₆alkanyl and oxo;
 6. The method of claim 1 wherein R³ is hydrogen. 7.The method of claim 1 wherein R⁴ is hydrogen.
 8. The method of claim 1wherein n is
 1. 9. The method of claim 1 wherein the pain is caused byheadache, earache, dysmenorrhea, arthralgia, myalgia, musculoskeletalpain, arthritis, immunizations, teething, tonsillectomy.
 10. The methodof claim 1 wherein the fever is caused by bacterial or viral infectionsand as a substitute for aspirin in upper GI disease, aspirin allergy,bleeding disorders, clients on anticoagulant therapy, and goutyarthritis.
 11. A method of controlling pain or fever in a subject inneed thereof comprising administering to the subject a compound ofFormula (II):

wherein: R¹ is a substituent independently selected from the groupconsisting of hydrogen and C₁₋₆alkanyl; R² is a substituentindependently selected from the group consisting of hydrogen,C₁₋₆alkanyl and dioxo; or R¹ and R² taken together with the atoms towhich they are attached form a radical selected from the groupconsisting of a 5 to 10 membered cycloheteroalkanyl, 5 to 10 memberedcycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein, inaddition to the heteroatom N, said radical may optionally contain 1 to 3additional heteroatoms, independently selected from the group consistingof O, N and S; additionally, said radical may be further optionallysubstituted with one to three substituents independently selected fromthe group consisting of C₁₋₆alkanyl and oxo; ⁴ is a substituent selectedfrom the group consisting of hydrogen, C₁₋₆alkanyl, C₁₋₆alkanyloxy,fluorinated alkanyl, fluorinated alkanyloxy, halogen, hydroxyl, nitro,amino, C₁₋₆alkanylamino; C₁₋₆dialkanylamino and cyano; n is an integerfrom 1 to 3; and enantiomers, diastereomers, tautomers, solvates, orpharmaceutically acceptable salts thereof.
 12. The method of claim 11wherein R¹ and R² taken together with the atoms to which they areattached form a 5 to 10 membered cycloheteroalkanyl or 5 to 10 memberedcycloheteroalkenyl radical, wherein, in addition to the heteroatom N,said radical may optionally contain 1 to 3 additional heteroatoms,independently selected from the group consisting of O, N and S;additionally, said radical may be further optionally substituted withone to three substituents independently selected from the groupconsisting of C₁₋₆alkanyl and oxo;
 13. The method of claim 11 wherein R¹and R² taken together with the atoms to which they are attached form a 5to 10 membered cycloheteroalkenyl, wherein, in addition to theheteroatom N, said radical may optionally contain 1 to 3 additionalheteroatoms, independently selected from the group consisting of O, Nand S; additionally, said radical may be further optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₆alkanyl and oxo;
 14. The method of claim 11 wherein R¹and R² taken together with the atoms to which they are attached form a 5to 10 membered heteroaryl radical, wherein, in addition to theheteroatom N, said radical may optionally contain 1 to 3 additionalheteroatoms, independently selected from the group consisting of O, Nand S; additionally, said radical may be further optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₆alkanyl and oxo;
 15. The method of claim 11 wherein R¹and R² taken together with the atoms to which they are attached form aradical selected from the group consisting of a 5 to 10 membered cycliheteroalkyl and a 5 to 10 membered heteroaryl; additionally, saidradical may be further optionally substituted with one to threesubstituents independently selected from the group consisting ofC₁₋₆alkanyl and oxo;
 16. The method of claim 11 wherein R⁴ is hydrogen.17. The method of claim 11 wherein n is
 1. 18. The method of claim 11wherein the pain is caused by headache, earache, dysmenorrhea,arthralgia, myalgia, musculoskeletal pain, arthritis, immunizations,teething, tonsillectomy.
 19. The method of claim 11 wherein the fever iscaused by bacterial or viral infections and as a substitute for aspirinin upper GI disease, aspirin allergy, bleeding disorders, clients onanticoagulant therapy, and gouty arthritis.
 20. A composition comprisingcompounds of Formula (I):

wherein R³ is hydrogen and R¹ and R² taken together form an optionallysubstituted pyrrole; and enantiomers, diastereomers, tautomers,solvates, or pharmaceutically acceptable salts thereof.
 21. A method ofcontrolling pain or fever in a subject in need thereof comprisingadministering to the subject a compound of Formula (I) wherein thecompound of formula (I) is selected from the group consisting of:Pyridine-2-carboxylic acid (4-hydroxy-phenyl )-amide;(S)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide;(R)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide;1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide;1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide;5-Methyl-1H-pyrazole-3-carboxylic acid (4-hydroxy-phenyl)-amide; and3H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide and enantiomers,diastereomers, tautomers, solvates, or pharmaceutically acceptable saltsthereof.
 22. A method of controlling pain or fever in a subject in needthereof comprising administering to the subject a compound of Formula(II) wherein the compound of formula (II) is selected from the groupconsisting of: N-(4-Hydroxy-phenyl)-2-mercapto-acetamide;N-(4-Hydroxy-phenyl)-2-methylsulfanyl-acetamide; andN-(4-Hydroxy-phenyl)-2-methanesulfonyl-acetamide; and enantiomers,diastereomers, tautomers, solvates, or pharmaceutically acceptable saltsthereof.
 23. A composition comprising compounds of Formula (I) whereinthe compounds are selected from the groupo consisting of:Pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide;(S)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide;(R)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide;1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide;1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide;5-Methyl-1H-pyrazole-3-carboxylic acid (4-hydroxy-phenyl)-amide; and3H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide; andenantiomers, diastereomers, tautomers, solvates, or pharmaceuticallyacceptable salts thereof.